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https://www.readbyqxmd.com/read/28529483/identification-of-a-novel-allosteric-inhibitory-site-on-tryptophan-hydroxylase-1-enabling-unprecedented-selectivity-over-all-related-hydroxylases
#1
Mike Petrassi, Rob Barber, Celine Be, Sarah Beach, Brian Cox, Anne-Marie D'Souza, Nick Duggan, Martin Hussey, Roy Fox, Peter Hunt, Gabor Jarai, Takatoshi Kosaka, Paul Oakley, Viral Patel, Neil Press, David Rowlands, Clemens Scheufler, Oliver Schmidt, Honnappa Srinivas, Mary Turner, Rob Turner, John Westwick, Alison Wolfreys, Nuzhat Pathan, Simon Watson, Matthew Thomas
Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements - SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28464229/functional-characterization-of-the-neuron-restrictive-silencer-element-in-the-human-tryptophan-hydroxylase-2-gene-expression
#2
Yukino Nawa, Hanae Kaneko, Masayuki Oda, Masaaki Tsubonoya, Tomoko Hiroi, Maria Teresa Gentile, Luca Colucci-D'Amato, Ryoya Takahashi, Hiroaki Matsui
Tryptophan hydroxylase 2 (TPH2) is the key enzyme in the synthesis of neuronal serotonin. Although previous studies suggest that TPH2 NRSE (neuron-restrictive silencer element) functions as a negative regulator dependent on NRSF (neuron-restrictive silencer factor) activity, the underlying mechanisms are yet to be fully elucidated. Here, we show a detailed analysis of the NRSE-mediated repression of the human TPH2 (hTPH2) promoter activity in RN46A cells, a cell line derived from rat raphe neurons. Quantitative real-time RT-PCR analysis revealed the expression of serotonergic marker genes (Mash1, Nkx2...
May 2, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28456685/association-of-regulatory-tph2-polymorphisms-with-higher-reduction-in-depressive-symptoms-in-children-and-adolescents-treated-with-fluoxetine
#3
Patricia Gassó, Natalia Rodríguez, Daniel Boloc, Ana Blázquez, Teresa Torres, Ana Gortat, Maria Teresa Plana, Amalia Lafuente, Sergi Mas, Luisa Lázaro
Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine...
April 26, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28443016/genetics-of-aggression-in-alzheimer-s-disease-ad
#4
Walter J Lukiw, Evgeny I Rogaev
Alzheimer's disease (AD) is a terminal, age-related neurological syndrome exhibiting progressive cognitive and memory decline, however AD patients in addition exhibit ancillary neuropsychiatric symptoms (NPSs) and these include aggression. In this communication we provide recent evidence for the mis-regulation of a small family of genes expressed in the human hippocampus that appear to be significantly involved in expression patterns common to both AD and aggression. DNA array- and mRNA transcriptome-based gene expression analysis and candidate gene association and/or genome-wide association studies (CGAS, GWAS) of aggressive attributes in humans have revealed a surprisingly small subset of six brain genes that are also strongly associated with altered gene expression patterns in AD...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28413824/perturbation-of-serotonin-homeostasis-during-adulthood-affects-serotonergic-neuronal-circuitry
#5
Marta Pratelli, Sara Migliarini, Barbara Pelosi, Francesco Napolitano, Alessandro Usiello, Massimo Pasqualetti
Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2(fl)°(x) conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28386236/metabolic-response-of-visceral-white-adipose-tissue-of-obese-mice-exposed-for-5-days-to-human-room-temperature-compared-to-mouse-thermoneutrality
#6
Inge van der Stelt, Femke Hoevenaars, Jitka Široká, Lidwien de Ronde, David Friedecký, Jaap Keijer, Evert van Schothorst
Housing of laboratory mice at room temperature (22°C) might be considered a constant cold stress, which induces a thermogenic program in brown adipose tissue (BAT). However, the early adaptive response of white adipose tissue (WAT), the fat storage organ of the body, to a change from thermoneutrality to room temperature is not known. This was investigated here for various WAT depots, focusing on epididymal WAT (eWAT), widely used as reference depot. Male adult diet-induced obese (DIO) C57BL/6JOlaHsd mice housed at thermoneutrality (29°C), were for 5 days either switched to room temperature (22°C) or remained at thermoneutrality...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28342337/nice-guys-homozygocity-for-the-tph2-703g-t-rs4570625-minor-allele-promotes-low-aggressiveness-and-low-anxiety
#7
Kariina Laas, Evelyn Kiive, Jarek Mäestu, Mariliis Vaht, Toomas Veidebaum, Jaanus Harro
BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. We examined whether the TPH2 polymorphism -703G/T (rs4570625) is associated with aggressiveness and impulsivity, and the prevalence of psychiatric disorders, in a population-representative sample. METHODS: We used self and proxy reports on aggressive behaviour in the younger birth cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study collected at age 25, and earlier collected impulsivity and related data of both ECPBHS cohorts...
March 19, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28320136/association-between-gene-polymorphism-and-depression-in-parkinson-s-disease-a-case-control-study
#8
Jinhua Zheng, Xinglong Yang, Quanzhen Zhao, Sijia Tian, Hongyan Huang, Yalan Chen, Yanming Xu
OBJECTIVE: To investigate possible associations of Parkinson's disease (PD) with polymorphism in depression-related genes and in the alpha-synuclein (SNCA) gene. METHODS: A consecutive series of patients with PD were divided into those with depression and those without it. Patients (330) were genotyped at four single-nucleotide polymorphisms (SNPs) in four genes previously associated with depression, as well as four SNPs in the PD-associated SNCA gene. RESULTS: Of 330 patients, 125 (37...
April 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28264500/geneanalytics-pathway-analysis-and-genetic-overlap-among-autism-spectrum-disorder-bipolar-disorder-and-schizophrenia
#9
Naveen S Khanzada, Merlin G Butler, Ann M Manzardo
Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e...
February 28, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28210624/rna-sequencing-analysis-reveals-interactions-between-breast-cancer-or-melanoma-cells-and-the-tissue-microenvironment-during-brain-metastasis
#10
Ryo Sato, Teppei Nakano, Mari Hosonaga, Oltea Sampetrean, Ritsuko Harigai, Takashi Sasaki, Ikuko Koya, Hideyuki Okano, Jun Kudoh, Hideyuki Saya, Yoshimi Arima
Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non-small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28197551/ephrina5-signaling-is-required-for-the-distinctive-targeting-of-raphe-serotonin-neurons-in-the-forebrain
#11
Teng Teng, Afsaneh Gaillard, Aude Muzerelle, Patricia Gaspar
Serotonin (5-HT) neurotransmission in the brain relies on a widespread axon terminal network originating from the hindbrain raphe nuclei. These projections are topographically organized such that the dorsal (DR), and median raphe (MnR) nuclei have different brain targets. However, the guidance molecules involved in this selective targeting in development are unknown. Here, we show the implication of ephrinA5 signaling in this process. We find that the EphA5 gene is selectively expressed in a subset of 5-HT neurons during embryonic and postnatal development...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28176268/no-genetic-association-between-attention-deficit-hyperactivity-disorder-adhd-and-parkinson-s-disease-in-nine-adhd-candidate-snps
#12
Julia M Geissler, Marcel Romanos, Manfred Gerlach, Daniela Berg, Claudia Schulte
Attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13)...
February 7, 2017: Attention Deficit and Hyperactivity Disorders
https://www.readbyqxmd.com/read/28161472/novel-serum-and-bile-protein-markers-predict-primary-sclerosing-cholangitis-disease-severity-and-prognosis
#13
Mette Vesterhus, Anders Holm, Johannes Roksund Hov, Ståle Nygård, Erik Schrumpf, Espen Melum, Liv Wenche Thorbjørnsen, Vemund Paulsen, Knut Lundin, Inge Dale, Odd Helge Gilja, Serge J L B Zweers, Morten Vatn, Frank G Schaap, Peter L M Jansen, Thor Ueland, Helge Røsjø, Bjørn Moum, Cyriel Y Ponsioen, Kirsten Muri Boberg, Martti Färkkilä, Tom H Karlsen, Fridtjof Lund-Johansen
BACKGROUND & AIMS: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC). METHODS: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls)...
June 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28069454/c1473g-polymorphism-in-mouse-tryptophan-hydroxylase-2-gene-in-the-regulation-of-the-reaction-to-emotional-stress
#14
Ekaterina Y Bazhenova, Daria V Bazovkina, Elizabeth A Kulikova, Dariya V Fursenko, Nikita V Khotskin, Daria V Lichman, Alexander V Kulikov
Neurotransmitter serotonin (5-HT) is involved in the regulation of stress response. Tryptophan hydroxylase-2 (TPH2) is the key enzyme of serotonin (5-HT) synthesis in the brain. C1473G polymorphism in Tph2 gene is the main factor defining the enzyme activity in the brain of laboratory mice. The effect of interaction between C1473G polymorphism and 30min restriction stress on the behavior in the open field test, c-Fos gene expression and 5-HT metabolism in the brain in adult male of B6-1473C and B6-1473G congenic mouse lines with high and low TPH2 activity was investigated...
January 6, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28068779/norepinephrine-transporter-gene-variants-and-remission-from-depression-with-venlafaxine-treatment-in-older-adults
#15
Victoria S Marshe, Malgorzata Maciukiewicz, Soham Rej, Arun K Tiwari, Etienne Sibille, Daniel M Blumberger, Jordan F Karp, Eric J Lenze, Charles F Reynolds, James L Kennedy, Benoit H Mulsant, Daniel J Müller
OBJECTIVE: The primary objective of this study was to investigate five putatively functional variants of the norepinephrine transporter (SLC6A2, NET) and serotonin transporter (SLC6A4, SERT) genes and remission in depressed older adults treated with venlafaxine. A secondary objective was to analyze 17 other variants in serotonergic system genes (HTR1A, HTR2A, HTR1B, HTR2C, TPH1, TPH2) potentially involved in the mechanism of action of venlafaxine. METHOD: The sample included 350 adults age 60 or older with DSM-IV-defined major depressive disorder and a score of at least 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS)...
May 1, 2017: American Journal of Psychiatry
https://www.readbyqxmd.com/read/28029782/a-tph2-gfp-reporter-stem-cell-line-to-model-in-vitro-and-in-vivo-serotonergic-neuron-development-and-function
#16
Giulia Pacini, Attilio Marino, Sara Migliarini, Elisa Brilli, Barbara Pelosi, Giacomo Maddaloni, Marta Pratelli, Mario Pellegrino, Aldo Ferrari, Massimo Pasqualetti
Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2(GFP), in which the vital reporter GFP replaces the tryptophan hydroxylase 2 (Tph2) gene...
January 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28012347/enhanced-dendritic-morphogenesis-of-adult-hippocampal-newborn-neurons-in-central-5-ht-deficient-mice
#17
Ning-Ning Song, Qiong Zhang, Ying Huang, Ling Chen, Yu-Qiang Ding, Lei Zhang
Serotonin (5-HT) plays an important role in regulating adult hippocampal neurogenesis. Chronic administration of selective 5-HT reuptake inhibitors (SSRIs), which up-regulates extracellular 5-HT concentration, accelerates the maturation of adult-born hippocampal neurons. It is unknown, however, about effects of central 5-HT-deficiency on the dendritic morphogenesis of these newborn neurons. Here, we address this question using two central 5-HT-deficient mouse models, Tph2 conditional knockout mice (CKO) losing central 5-HT from embryonic stage, and Pet1-Cre;Rosa26-DTR (diphtheria toxin receptor) mice lacking central 5-HT neurons exclusively in adulthood...
December 15, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/28008302/benefits-of-hormone-therapy-estrogens-depend-on-estrogen-type-17%C3%AE-estradiol-and-conjugated-equine-estrogens-have-differential-effects-on-cognitive-anxiety-like-and-depressive-like-behaviors-and-increase-tryptophan-hydroxylase-2-mrna-levels-in-dorsal-raphe-nucleus
#18
Ryoko Hiroi, Giulia Weyrich, Stephanie V Koebele, Sarah E Mennenga, Joshua S Talboom, Lauren T Hewitt, Courtney N Lavery, Perla Mendoza, Ambra Jordan, Heather A Bimonte-Nelson
Decreased serotonin (5-HT) function is associated with numerous cognitive and affective disorders. Women are more vulnerable to these disorders and have a lower rate of 5-HT synthesis than men. Serotonergic neurons in the dorsal raphe nucleus (DRN) are a major source of 5-HT in the forebrain and play a critical role in regulation of stress-related disorders. In particular, polymorphisms of tryptophan hydroxylase-2 (TpH2, the brain-specific, rate-limiting enzyme for 5-HT biosynthesis) are implicated in cognitive and affective disorders...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27989490/paraphilic-sexual-offenders-do-not-differ-from-control-subjects-with-respect-to-dopamine-and-serotonin-related-genetic-polymorphisms
#19
Andrzej Jakubczyk, Aleksandra Krasowska, Marcin Bugaj, Maciej Kopera, Anna Klimkiewicz, Agata Łoczewska, Aneta Michalska, Aleksandra Majewska, Natalia Szejko, Anna Podgórska, Małgorzata Sołowiej, Leszek Markuszewski, Sławomir Jakima, Rafał Płoski, Kirk Brower, Marcin Wojnar
INTRODUCTION: Rape and pedophilic child molestation are the most commonly convicted sexual offenses in Poland. Recent studies have suggested a possible genetic contribution toward pathologic sexual interests and behaviors. AIM: To analyze and compare functional polymorphisms of genes associated with the activity of the serotonin and dopamine systems in a group of paraphilic sexual offenders and control subjects. METHODS: The study sample (n = 97) consisted of two groups: paraphilic sexual offenders (65 pedophilic child molesters and 32 rapists) and controls (n = 76)...
January 2017: Journal of Sexual Medicine
https://www.readbyqxmd.com/read/27973928/tyrosine-and-tryptophan-hydroxylases-as-therapeutic-targets-in-human-disease
#20
Kai Waløen, Rune Kleppe, Aurora Martinez, Jan Haavik
The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function...
December 26, 2016: Expert Opinion on Therapeutic Targets
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